Potential inhibition pathways

Besides modification of the glycan, other strategies to overcome vancomycin resistance have been undertaken. Dimeric and trimeric vancomycin constructs bind the D-Ala-D-Ala peptide more tightly than vancomycin itself and have shown antibacterial activity against vancomycin resistant strains [169,170,171]. A potential inhibition pathway that acts through dimerization and membrane-anchoring is also being actively pursued [172,173]. 

Scheme 1 Potential inhibition pathways to hemozoin aggregation...

Yarbrough WM, Mukherjee R, Escobar GP, Sample JA, McLean JE, Dowdy KB, et al. Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling A potentially novel pathway. J Thorac Cardiovasc Surg 2003 126 1892-1899. 

The ability of the drug in question to inhibit the activities of known pathways for drug metabolism is evaluated. If a drug is an inhibitor of a drug-metabolizing enzyme pathway, it will have the potential to cause inhibitory drug interactions with coadministered drugs that are substrates of the inhibited pathway. 

In addition to these covalent modifications, bovine and P. aeruginosa DDAH can also be inhibited by Zn(II) binding at the active site (Figure 14(b)). Therefore, release of zinc during periods of oxidative stress may also be a potential cause of DDAH inhibition." Further studies will be required to determine which of these inhibition pathways, or others, occur in vivo during normal and pathophysiology. 

Figure 1. A) Serpin binding to target proteases occurs via interaction of the protease with the RSL PI-PI scissiie bond. This interaction can result in either (1) a form of suicide inhibition wherein the serpin RSL is cleaved, but the protease remains bound to the serpin and is dragged across the face of the serpin to remain stuck to the opposite pole of the serpin (top serpin/ protease interactive pathway) or (2) the serpin RSL is cleaved and the serpin rendered inactive (the bottom serpin/protease interactive pathway). B) Diagram of thrombotic and thrombolytic pathways as well as potential targeted pathways for the mammalian, PAI-1 and viral, Serp-1, serpins in an injured arterial wall.

Biorational approaches have proven useful in the development of classes of herbicides which inhibit essential metaboHc pathways common to all plants and thus are specific to plants and have low toxicity to mammalian species. Biorational herbicide development remains a high risk endeavor since promising high activities observed in the laboratory may be nullified by factors such as limitations in plant uptake and translocation, and the instabiHty or inactivity of biochemical en2yme inhibitors under the harsher environmental conditions in the field. Despite these recogni2ed drawbacks, biorational design of herbicides has shown sufficient potential to make the study of herbicide modes of action an important and growing research area. 

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